Department of Medicine, Division of Clinical Immunology and Allergy, McMaster University, Hamilton, Ontario, Canada.
Centre for Heart Lung Innovation, University of British Columbia, St Paul's Hospital, Vancouver, British Columbia, Canada.
Mucosal Immunol. 2015 Sep;8(5):993-9. doi: 10.1038/mi.2014.126. Epub 2014 Dec 17.
Recent candidate gene and genome-wide association studies have identified "protective" associations between the single-nucleotide polymorphism (SNP) rs1837253 in the TSLP gene and risk for allergy, asthma, and airway hyperresponsiveness. The absence of linkage disequilibrium of rs1837253 with other SNPs in the region suggests it is likely a causal polymorphism for these associations, having functional consequences. We hypothesized that rs1837253 genotype would influence TSLP secretion from mucosal surfaces. We therefore evaluated the secretion of TSLP protein from primary nasal epithelial cells (NECs) of atopic and nonatopic individuals and its association with rs1837253 genotype. We found that although atopic sensitization does not affect the secretion of TSLP from NECs, there was decreased TSLP secretion in NECs obtained from heterozygous (CT; 1.8-fold) and homozygous minor allele (TT; 2.5-fold) individuals, as compared with NECs from homozygous major allele individuals (CC; P<0.05), after double-stranded RNA (dsRNA) stimulation (50 μg ml(-1)). Our novel results show that rs1837253 polymorphism may be directly involved in the regulation of TSLP secretion. This may help explain the protective association of this genetic variant with asthma and related traits. Identifying functional consequences of SNPs in genes with previously reported clinical associations is critical in understanding and targeting allergic inflammation.
最近的候选基因和全基因组关联研究已经确定了 TSLP 基因中单核苷酸多态性 (SNP) rs1837253 与过敏、哮喘和气道高反应性风险之间的“保护”关联。rs1837253 与该区域其他 SNPs 之间不存在连锁不平衡表明，它很可能是这些关联的因果多态性，具有功能后果。我们假设 rs1837253 基因型会影响 TSLP 从黏膜表面的分泌。因此，我们评估了特应性和非特应性个体的原代鼻上皮细胞 (NEC) 中 TSLP 蛋白的分泌及其与 rs1837253 基因型的关系。我们发现，尽管特应性致敏不会影响 NEC 中 TSLP 的分泌，但与纯合主要等位基因个体 (CC) 的 NEC 相比，杂合子 (CT; 1.8 倍) 和纯合子 minor 等位基因 (TT; 2.5 倍) 的 NEC 中 TSLP 的分泌减少(P<0.05)，在双链 RNA (dsRNA) 刺激 (50 μg ml(-1)) 后。我们的新结果表明，rs1837253 多态性可能直接参与 TSLP 分泌的调节。这可能有助于解释该遗传变异与哮喘和相关特征的保护性关联。确定具有先前报道临床关联的基因中 SNPs 的功能后果对于理解和靶向过敏炎症至关重要。
